There is a great need for controlled release formulations for BASs such as proteins, peptides and other drugs that are administered parenterally. Despite many published approaches, there is no entirely satisfactory technology.
Several features are desirable, alone or in combination, in such a technology. For example, it is desirable that the materials that are being used, often polymers, are approved by the regulatory authorities. In addition, it is desirable that the encapsulation of the BAS is done at high efficiency and retention of the integrity of the BAS, for example measured in terms of bioactivity. For BASs such as proteins that are dependent on their three-dimensional structure for retention of biological activity and for avoidance of, for example, undesired immune responses, it is desirable that the manufacturing process is able to retain the integrity of the substance. It is also desirable to control the release kinetics of the substance after administration, and in addition to the duration of the release, it is the variation of the release rate that is relevant. It is desirable to avoid too high a release initially after administration, which may lead to adverse effects and wasting of the BAS. Another feature that can be desirable, alone or in combination with one or more of those listed above or other features, is that the technology provide adequate release of the drug both when the content of drug in the formulation is low and high.
Injectable microcapsules comprising a core of highly branched, high molecular weight amylopectin and hGH and further comprising a release-controlling shell of a drug-free polymer are known (Reslow et al., Sustained release of human growth hormone (hGH) from PLG-coated starch microspheres. Drug Delivery Systems and Sciences, 2002, 2, 1 103-109).
A known technology for manufacturing of such coated microcapsules employs highly branched starch in an aqueous two-phase system (emulsion) where the solidification of droplets to microcapsules is obtained through the natural ability of the starch to gel (WO 97/14408, WO 02/28370), followed by coating using air suspension technology. This makes it possible to avoid exposing the BAS to an organic solvent. The long process time, however, is a disadvantage. Moreover, only one polymer, i.e. high molecular weight highly branched starch, is believed to have been demonstrated to work with this technology. In WO 02/28908, WO 02/28909 and WO 02/28370, highly specific requirements are described for this starch in order to manufacture parenterally administrable microcapsules and it is stated that the concentration of starch should be at least 20% for the manufacture of starch microparticles having good properties. Yet, the specific starch is not approved for parenteral administration by the regulatory authorities, and it can only be manufactured by a complicated purification process. In some cases it is desirable to have a higher content of biologically active substance than has been, or can be, obtained with this technology.
According to WO 02/28370, it is necessary that the solidification occurs through the natural tendency or ability of starch to gel, and not through, for example, precipitation with organic solvents.
Although many advances in controlled-release formulations for biologically active substances, including those for parenteral administration, are known, improvements would be desirable.